[go: up one dir, main page]

US20090326005A1 - Quinine sulfate/bisulfate solid complex; methods of making; and methods of use thereof - Google Patents

Quinine sulfate/bisulfate solid complex; methods of making; and methods of use thereof Download PDF

Info

Publication number
US20090326005A1
US20090326005A1 US12/491,311 US49131109A US2009326005A1 US 20090326005 A1 US20090326005 A1 US 20090326005A1 US 49131109 A US49131109 A US 49131109A US 2009326005 A1 US2009326005 A1 US 2009326005A1
Authority
US
United States
Prior art keywords
solid complex
quinine sulfate
quinine
guest
acetic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
US12/491,311
Other versions
US8258155B2 (en
Inventor
Tong Sun
Shawn Watson
Wei Lai
Stephan D. PARENT
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sun Pharmaceutical Industries Inc
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US12/491,311 priority Critical patent/US8258155B2/en
Application filed by Individual filed Critical Individual
Assigned to MUTUAL PHARMACEUTICAL COMPANY, INC. reassignment MUTUAL PHARMACEUTICAL COMPANY, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LAI, WEI, PARENT, STEPHAN D., SUN, TONG, WATSON, SHAWN
Assigned to UBS AG, STAMFORD BRANCH, AS COLLATERAL AGENT reassignment UBS AG, STAMFORD BRANCH, AS COLLATERAL AGENT PATENT SECURITY AGREEMENT Assignors: MUTUAL PHARMACEUTICAL COMPANY, INC.
Publication of US20090326005A1 publication Critical patent/US20090326005A1/en
Assigned to MUTUAL PHARMACEUTICAL COMPANY, INC., A PENNSYLVANIA CORPORATION reassignment MUTUAL PHARMACEUTICAL COMPANY, INC., A PENNSYLVANIA CORPORATION RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: UBS AG, STAMFORD BRANCH, A SWISS BANKING INSTITUTION
Publication of US8258155B2 publication Critical patent/US8258155B2/en
Application granted granted Critical
Assigned to MPC OLDCO, INC. reassignment MPC OLDCO, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: MUTUAL PHARMACEUTICAL COMPANY, INC.
Assigned to MUTUAL PHARMACEUTICAL COMPANY, INC. reassignment MUTUAL PHARMACEUTICAL COMPANY, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MPC OLDCO, INC.
Assigned to SUN PHARMACEUTICAL INDUSTRIES, INC. reassignment SUN PHARMACEUTICAL INDUSTRIES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MUTUAL PHARMACEUTICAL COMPANY, INC.
Expired - Fee Related legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Quinine(cinchonan-9-ol, 6′-methoxy-, (8 ⁇ ,9R)—) is an antiprotozoal and an antimyotonic, and is known for the treatment of malaria caused by Plasmodium species, the treatment of nocturnal recumbency leg muscle cramps, and the treatment of babesiosis caused by Babesia microti.
  • quinine hydrochloride Various salts of quinine are known including quinine hydrochloride, and quinine sulfate. Crystalline quinine sulfate is known to exhibit low solubility in water at room temperature.
  • Different crystalline forms, non-crystalline forms, hydrates and solvates of an active agent can exhibit vastly different physical properties such as solubility, melting point, hardness, optical properties, dissolution, and the like. These differences such as varying dissolution can result in differences in the therapeutic activity.
  • a thorough understanding of the various crystalline forms, non-crystalline forms, hydrates and solvates of an active agent is an important consideration in formulating the active agent, specifically when trying to achieve consistency of any resulting pharmaceutical product batch to batch.
  • a solid complex comprises quinine sulfate/bisulfate and a guest, wherein the guest is acetic acid or DL-tartaric acid.
  • a composition comprises a solid complex comprising quinine sulfate/bisulfate and a guest, wherein the guest is acetic acid or DL-tartaric acid; and a pharmaceutically acceptable excipient.
  • a method of preparing a solid complex comprises milling a combination of quinine sulfate and acetic acid to form quinine sulfate acetic acid solid complex.
  • a method of preparing a solid complex comprises preparing quinine sulfate acetic acid solid complex by liquid diffusion in ethyl acetate.
  • a method of preparing a solid complex comprises crystallizing a solid complex from a solution containing quinine sulfate, a guest, and optionally a solvent system with optionally evaporating the solvent system from the solution, wherein the guest is DL-tartaric acid.
  • a method of preparing a solid complex comprises adding an anti-solvent to a solution containing quinine sulfate, a guest, and optionally a solvent system; and precipitating a quinine sulfate solid complex, wherein the guest is acetic acid.
  • a method of preparing a solid complex comprises dissolving quinine sulfate and tartaric acid in a lower alkyl alcohol with heating; allowing the solid complex to precipitate.
  • FIG. 1 illustrates XRPD pattern of quinine sulfate acetic acid solid complex.
  • FIG. 2 illustrates FT-Raman spectrum of quinine sulfate acetic acid solid complex.
  • FIG. 3 illustrates XRPD pattern of quinine bisulfate tartaric acid solid complex.
  • FIG. 4 illustrates FT-Raman spectrum of quinine bisulfate tartaric acid solid complex.
  • novel quinine sulfate and quinine bisulfate solid complexes Disclosed herein are novel quinine sulfate and quinine bisulfate solid complexes, methods of preparing the solid complexes, compositions prepared therefrom, and uses thereof. It has been unexpectedly discovered herein that quinine sulfate salts (e.g., quinine sulfate and quinine bisulfate) can exist as a solid complex (e.g., a co-crystal) with a guest molecule. Novel solid complexes disclosed herein include quinine sulfate acetic acid and quinine bisulfate tartaric acid.
  • quinine sulfate salts e.g., quinine sulfate and quinine bisulfate
  • Novel solid complexes disclosed herein include quinine sulfate acetic acid and quinine bisulfate tartaric acid.
  • Solid complex means a solid form containing quinine sulfate/bisulfate and an additional component (“guest”) which interact with one another to result in a solid material having a different physicochemical property than the corresponding free quinine sulfate/bisulfate.
  • the interactions between the quinine sulfate/bisulfate and the guest can be hydrogen bonding, van der Waals interactions, electrostatic interactions, hydrophobic interactions a combination thereof, and the like.
  • Exemplary solid complexes include co-crystals (i.e. a crystalline supramolecular complex), single phase molecular dispersions, and the like.
  • the properties can include solubility, melting point, spectroscopic, etc.
  • the solid complex may include one or more solvate or water molecules in the crystalline lattice (e.g., solvates or hydrates of co-crystals, or a co-crystal further comprising a solvent or water molecule).
  • solvate or water molecules in the crystalline lattice e.g., solvates or hydrates of co-crystals, or a co-crystal further comprising a solvent or water molecule.
  • Quinine sulfate and quinine bisulfate are inclusive of all crystalline forms including all polymorphs, non-crystalline forms, anhydrous forms, hydrates such as the dihydrate, and solvates unless specifically indicated otherwise.
  • Quinine sulfate/bisulfate means quinine sulfate or quinine bisulfate. Specific polymorphs of quinine sulfate include those disclosed in co-pending Provisional Application Ser. No.
  • “Guest” means an organic acid, specifically acetic acid, gentisic acid, DL-mandelic acid, salicylic acid, or DL-tartaric acid.
  • the ratio of quinine sulfate/bisulfate to guest may be for example, 1:1, 1:1.5 and 1:2. In certain embodiments, the ratio is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10 quinine sulfate/bisulfate to guest. In other embodiments, the ratio is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10 guest to quinine sulfate/bisulfate.
  • the solid complexes can be physically distinguished from crystalline quinine sulfate/bisulfate using a variety of analytical tools and characterization methods, such as, for example, Raman spectroscopy, IR spectroscopy (IR, FT-IR), X-ray powder diffraction (XPRD) crystallography, X-ray crystallography, neutron diffraction, Synchrotron radiation, solid state NMR spectroscopy, differential scanning calorimetry (DSC), Thermogravimetric analysis (TGA), Thermogravimetric/infrared analysis (TG-IR), melting point, and heats of fusion.
  • analytical tools and characterization methods such as, for example, Raman spectroscopy, IR spectroscopy (IR, FT-IR), X-ray powder diffraction (XPRD) crystallography, X-ray crystallography, neutron diffraction, Synchrotron radiation, solid state NMR spectroscopy, differential scanning calorimetry (DSC), Thermog
  • the quinine sulfate/bisulfate solid complexes can be prepared using a variety of methods including antisolvent precipitation, slow cooling of a solution of quinine sulfate and guest, precipitation from a solution of quinine sulfate and guest at a constant temperature, seeding solutions of quinine sulfate and guest with optional cooling, slurrying and the like.
  • Exemplary methods for preparing solid complexes include mechanical and solvent processes.
  • Exemplary mechanical processes include milling/grinding, and extrusion; and exemplary solvent processes include dissolving, partially dissolving (and optionally sonicating) in a common solvent, followed by solvent evaporation or spray-drying; or a combination thereof.
  • the process can be conducted under inert atmosphere (e.g., nitrogen, argon atmospheres).
  • the quinine sulfate solid complex can be prepared by a milling process.
  • the milling process generally involves grinding quinine sulfate and a guest in a mill, e.g., use of a ball mill, jet mill, impact mill, hammer mill, and the like.
  • the grinding can be performed with heating.
  • the quinine sulfate or guest can be in crystalline form, solid non-crystalline form, liquid, or the like.
  • the milling process can include grinding for about 10 seconds to about 2 hours, specifically about 1 minute to about 90 minutes, and more specifically about 20 minutes to about 60 minutes.
  • the solvent process generally involves preparing a solution or suspension of quinine sulfate/bisulfate and guest in a solvent system followed by optional removal of the solvent.
  • solution process both quinine sulfate/bisulfate and guest are completely dissolved in the solvent system.
  • the quinine sulfate/bisulfate or guest can remain partially undissolved.
  • solvent system means a single or a combination of two or more solvents.
  • Suitable solvents for preparing the quinine sulfate/bisulfate solid complex include those that do not adversely affect the stability of the quinine sulfate/bisulfate, guest or solid complex, and are preferably inert.
  • Suitable solvents may be organic, aqueous, or a mixture thereof
  • Suitable organic solvents may be aliphatic alcohols such as methanol (MeOH), ethanol (EtOH), n-propanol, isopropanol (IPA), n-butanol, tert-amyl alcohol (t-AmOH), tert-butyl alcohol, triflouroethanol, and 2-ethoxyethanol, particularly lower alkyl (C 1 -C 6 ) alcohols; ethers such as tetrahydrofuran (THF), dioxane, methyl-tert-butyl ether, 1,2-dimethoxyethane (DME), and 2-methyl tetrahydrofuran;
  • the solution prior to any solids formation, can be filtered to remove any undissolved solids, solid impurities and the like prior to removal of the solvent.
  • Any filtration system and filtration techniques known in the art can be used.
  • the solutions or suspensions can be seeded with the desired quinine sulfate solid complex.
  • the solutions or suspensions can be sonicated.
  • the solvent system of the solution or suspension of quinine sulfate/bisulfate, guest, and solvent system is removed slowly or rapidly. Rapid removal of the solvent system can be achieved in less than a minute by processes such as spray drying. Slow removal of the solvent system can be achieved in a minute or greater using methods such as evaporation under reduced pressure or evaporation at atmospheric pressure. Removal of the solvent system can be achieved with optional heating.
  • a quinine sulfate acetic acid solid complex exhibits XRPD peak positions at 8.4, 15.2, 16.6, 17.0, 17.8, 19.3, 20.4, 23.8, 25.2, and 25.7 ⁇ 0.1 degree 2-theta.
  • a quinine sulfate acetic acid solid complex exhibits the XRPD peak positions in Table 4 below.
  • a quinine sulfate acetic acid solid complex exhibits an X-ray powder diffraction pattern which is substantially similar to FIG. 1 .
  • a quinine sulfate acetic acid solid complex exhibits FT-Raman peaks at 1364, 1429, 1445, and 2954 ⁇ 4 cm ⁇ 1 .
  • a quinine sulfate acetic acid solid complex exhibits FT-Raman peaks in Table 5 below.
  • a quinine sulfate acetic acid solid complex exhibits a FT-Raman spectrum which is substantially similar to FIG. 2 .
  • a solid complex of quinine sulfate is quinine sulfate acetic acid co-crystal, specifically quinine sulfate acetic acid co-crystal monohydrate (2quinine.H 2 SO 4 .CH 3 COOH.H 2 O).
  • the quinine sulfate acetic acid co-crystal exhibits water solubility at room temperature of about 2 milligrams per milliliter.
  • a quinine bisulfate tartaric acid solid complex exhibits XRPD peak positions at 9.4, 10.4, 13.8, 15.2, 15.6, 16.8, 17.4, 18.7, 19.5, and 20.5 ⁇ 0.1 degrees 2-theta.
  • a quinine bisulfate tartaric acid solid complex exhibits the XRPD peak positions in Table 9 below.
  • a quinine bisulfate tartaric acid solid complex exhibits an X-ray powder diffraction pattern which is substantially similar to FIG. 3 .
  • a quinine bisulfate tartaric acid solid complex exhibits FT-Raman peaks at 767, 1386, 1431, and 1622 ⁇ 4 cm ⁇ 1 .
  • a quinine bisulfate tartaric acid solid complex exhibits FT-Raman peaks in Table 10 below.
  • a quinine bisulfate tartaric acid solid complex exhibits a FT-Raman spectrum which is substantially similar to FIG. 4 .
  • a solid complex of quinine sulfate/bisulfate is quinine bisulfate tartaric acid co-crystal.
  • the quinine bisulfate tartaric acid co-crystal exhibits solubility in water at room temperature of about 200 milligrams per milliliter.
  • compositions comprising the quinine sulfate/bisulfate solid complexes prepared herein.
  • Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, powders, and granules.
  • the solid complex may be admixed with one or more of the following: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders, such as carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f solution retarders, such as paraffin; (g) absorption accelerators, such as quaternary ammonium compounds; (h)
  • oral dosage form is meant to include a unit dosage form for oral administration.
  • An oral dosage form may optionally comprise a plurality of subunits such as, for example, microcapsules or microtablets. Multiple subunits may be packaged for administration in a single dose.
  • subunit is meant to include a composition, mixture, particle, pellet, etc., that can provide an oral dosage form alone or when combined with other subunits.
  • compositions can be immediate-release forms or controlled-release forms.
  • immediate-release is meant a conventional or non-modified release in which greater then or equal to about 75% of the active agent is released within two hours of administration, specifically within one hour of administration.
  • controlled-release is meant a dosage form in which the release of the active agent is controlled or modified over a period of time. Controlled can mean, for example, sustained-, delayed- or pulsed-release at a particular time. Alternatively, controlled can mean that the release of the active agent is extended for longer than it would be in an immediate-release dosage form, e.g., at least over several hours.
  • Dosage forms can be combination dosage forms having both immediate-release and controlled-release characteristics, for example, a combination of immediate-release pellets and controlled-release pellets.
  • the immediate-release portion of a combination dosage form may be referred to as a loading dose.
  • compositions described herein may be “coated”.
  • the coating may be a suitable coating, such as, a functional or a non-functional coating, or multiple functional or non-functional coatings.
  • functional coating is meant to include a coating that modifies the release properties of the total composition, for example, a sustained-release coating.
  • non-functional coating is meant to include a coating that is not a functional coating, for example, a cosmetic coating.
  • a non-functional coating can have some impact on the release of the active agent due to the initial dissolution, hydration, perforation of the coating, etc., but would not be considered to be a significant deviation from the non-coated composition.
  • the solid complexes of quinine sulfate and the compositions disclosed herein are useful for example to treat or for the prophylaxis of malaria caused by Plasmodium species (e.g., falciparum, vivax, and the like), uncomplicated Plasmodium falciparum malaria, severe or complicated Plasmodium falciparum malaria; the treatment or prophylaxis of leg muscle cramps (e.g., nocturnal recumbency leg muscle cramps), and the treatment of babesiosis caused by Babesia microti.
  • Plasmodium species e.g., falciparum, vivax, and the like
  • uncomplicated Plasmodium falciparum malaria severe or complicated Plasmodium falciparum malaria
  • leg muscle cramps e.g., nocturnal recumbency leg muscle cramps
  • babesiosis caused by Babesia microti.
  • Malaria is a parasitic disease caused by the Plasmodium species P. falciparum, P. vivax, P. ovale and P. malariae. Malaria parasites are transmitted by female Anopheles mosquitoes. Without being held to theory, it is believed that quinine toxic to the malaria parasite, specifically by interfering with the parasite's ability to break down and digest hemoglobin, thus starving the parasite or causing the build-up of toxic levels of partially degraded hemoglobin.
  • Nocturnal recumbency leg muscle cramps a common complaint in the elderly, is manifested as painful, involuntary contractions in the lower extremities after recumbency.
  • Quinine can be used for the treatment of leg cramps including those associated with arthritis, diabetes, varicose veins, thrombophlebitis, arteriosclerosis and static foot deformities.
  • Babesiosis is caused by Babesia microti.
  • the definitive host is a tick, in this case the deer tick, Ixodes dammini ( I. scapularis ). Humans enter the cycle when bitten by infected ticks; during a blood meal, a Babesia -infected tick introduces sporozoites into the human host.
  • X-ray powder diffraction analyses are performed on an Inel XRG-3000 diffractometer, equipped with a curved position-sensitive detector with a 2-theta range of 120°.
  • Real time data is collected using Cu Ka radiation at a resolution of 0.03° 2-theta.
  • the tube voltage and amperage are set to 40 kV and 30 mA, respectively.
  • Samples are prepared for analysis by packing them into thin-walled glass capillaries. Each capillary is mounted onto a goniometer head that is motorized to permit spinning of the capillary during data acquisition. Instrument calibration is performed daily using a silicon reference standard.
  • Peak lists are generated by using FileMonkey v3.2.0, Notepad v5.1, Dash v3.1, EXCEL 2003, and PatternMatch 2.3.6.
  • the XRPD patterns are background-corrected and prominent peaks are selected with the following parameters in Dash v3.1 (wavelength 1.541874 ⁇ , 15 iterations, 150 window, Monte Carlo, Smooth w/5 window). Peak positions are rounded to the nearest 0.1° 2-theta, relative intensities are rounded to the nearest 1%, peaks with a relative intensity less than 10% are removed, and peaks above 26° 2 ⁇ are also removed.
  • DSC Differential scanning calorimetry
  • Thermogravimetry (TG) analyses are carried out on a TA Instruments 2950 thermogravimetric analyzer.
  • the calibration standards are nickel and AlumelTM. Each sample is place in an aluminum sample pan and inserted into the TG furnace. Samples are started at ambient and then heated under a stream of nitrogen at a heating rate of 10° C./min, up to a final temperature of 175 or 350° C.
  • FT-Raman spectra are obtained using a FT-Raman 960 spectrometer (Thermo Nicolet) using an excitation wavelength of 1064 nm. Approximately 0.3 W of Nd:YVO 4 laser power is used to irradiate the sample. The Raman spectra are measured with a germanium (Ge) detector. The samples are prepared for analysis by placing the material in a glass tube and positioning the tube in a gold-coated tube holder in the accessory. A total of 256 sample scans are collected from 3600-100 cm ⁇ 1 at a spectral resolution of 4 cm ⁇ 1 , using Happ-Genzel apodization. Wavelength calibration is performed using sulfur. Data are analyzed and peak lists are generated by using Omic v. 7.2 software.
  • a generalized milling process involves placing approximately equal amounts of quinine sulfate and respective guest compounds into an agate milling holder with a milling ball for milling at ambient temperature.
  • the sample is dry milled.
  • the sample is milled for specific time intervals (2 and 20 minutes) at 30 Hz using a Retsch MM200 mixer mill.
  • the vial is opened and solids scraped from the side of the milling holder and ball in 5 minutes increments for the 20 minute grinding experiments.
  • Antisolvent Crystallization Solutions are prepared in various solvents at ambient temperatures and filtered through a 0.2- ⁇ m nylon filter. Antisolvent is then added and the solution is allowed to stand at ambient.
  • Ambient Crystallization Solutions are prepared in various solvents at ambient temperatures and filtered through a 0.2- ⁇ m nylon filter. The solutions are then allowed to stand at ambient.
  • Crash Cool Solutions are prepared in various solvents at elevated temperatures and filtered through a 0.2- ⁇ m nylon filter into a vial. Vials are then either left at ambient or placed in the refrigerator or a freezer.
  • Liquid Diffusion Solutions were prepared and filtered through a 0.2- ⁇ m nylon filter. The filtered solution was allowed to diffuse into an antisolvent in a small glass tube at ambient temperature. The anti-solvent used is miscible with the solvent and the tubes are left vertically and undisturbed at ambient.
  • SC Slow Cool Solutions are prepared using various solvents at elevated temperatures and filtered through a 0.2- ⁇ m nylon filter into an open vial while still warm. The vial is allowed to cool slowly to room temperature. The presence or absence of solids is noted. If there are no solids present, or if the amount of solids is judged too small for XRPD analysis, the vial is placed in a refrigerator. Again, the presence or absence of solids is noted and if there were none, the vial was placed in a freezer. Solids that formed are isolated by filtration and allowed to dry prior to analysis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)

Abstract

Disclosed are new quinine sulfate/bisulfate solid complexes, methods of making the solid complexes as well as formulations prepared therefrom and uses thereof.

Description

    CROSS REFERENCE TO RELATED APPLICATION
  • This application claims the benefit of U.S. Provisional Application Ser. No. 61/076,780 filed Jun. 30, 2008, which is hereby incorporated by reference in its entirety.
    • BACKGROUND
  • Quinine(cinchonan-9-ol, 6′-methoxy-, (8α,9R)—) is an antiprotozoal and an antimyotonic, and is known for the treatment of malaria caused by Plasmodium species, the treatment of nocturnal recumbency leg muscle cramps, and the treatment of babesiosis caused by Babesia microti.
  • Various salts of quinine are known including quinine hydrochloride, and quinine sulfate. Crystalline quinine sulfate is known to exhibit low solubility in water at room temperature.
  • Different crystalline forms, non-crystalline forms, hydrates and solvates of an active agent can exhibit vastly different physical properties such as solubility, melting point, hardness, optical properties, dissolution, and the like. These differences such as varying dissolution can result in differences in the therapeutic activity. A thorough understanding of the various crystalline forms, non-crystalline forms, hydrates and solvates of an active agent is an important consideration in formulating the active agent, specifically when trying to achieve consistency of any resulting pharmaceutical product batch to batch.
  • There remains a need in the art for new solid forms of quinine having improved properties of solubility, stability, processability and the like.
    • SUMMARY
  • In one embodiment, a solid complex comprises quinine sulfate/bisulfate and a guest, wherein the guest is acetic acid or DL-tartaric acid.
  • In another embodiment, a composition comprises a solid complex comprising quinine sulfate/bisulfate and a guest, wherein the guest is acetic acid or DL-tartaric acid; and a pharmaceutically acceptable excipient.
  • In yet another embodiment, a method of preparing a solid complex comprises milling a combination of quinine sulfate and acetic acid to form quinine sulfate acetic acid solid complex.
  • In still another embodiment, a method of preparing a solid complex comprises preparing quinine sulfate acetic acid solid complex by liquid diffusion in ethyl acetate.
  • In another embodiment, a method of preparing a solid complex comprises crystallizing a solid complex from a solution containing quinine sulfate, a guest, and optionally a solvent system with optionally evaporating the solvent system from the solution, wherein the guest is DL-tartaric acid.
  • In yet another embodiment, a method of preparing a solid complex comprises adding an anti-solvent to a solution containing quinine sulfate, a guest, and optionally a solvent system; and precipitating a quinine sulfate solid complex, wherein the guest is acetic acid.
  • In one embodiment, a method of preparing a solid complex comprises dissolving quinine sulfate and tartaric acid in a lower alkyl alcohol with heating; allowing the solid complex to precipitate.
  • These and other embodiments, advantages and features of the present invention become clear when detailed description and examples are provided in subsequent sections.
    • BRIEF DESCRIPTION OF DRAWINGS
  • FIG. 1 illustrates XRPD pattern of quinine sulfate acetic acid solid complex.
  • FIG. 2 illustrates FT-Raman spectrum of quinine sulfate acetic acid solid complex.
  • FIG. 3 illustrates XRPD pattern of quinine bisulfate tartaric acid solid complex.
  • FIG. 4 illustrates FT-Raman spectrum of quinine bisulfate tartaric acid solid complex.
    •  DETAILED DESCRIPTION
  • Disclosed herein are novel quinine sulfate and quinine bisulfate solid complexes, methods of preparing the solid complexes, compositions prepared therefrom, and uses thereof. It has been unexpectedly discovered herein that quinine sulfate salts (e.g., quinine sulfate and quinine bisulfate) can exist as a solid complex (e.g., a co-crystal) with a guest molecule. Novel solid complexes disclosed herein include quinine sulfate acetic acid and quinine bisulfate tartaric acid.
  • “Solid complex” means a solid form containing quinine sulfate/bisulfate and an additional component (“guest”) which interact with one another to result in a solid material having a different physicochemical property than the corresponding free quinine sulfate/bisulfate. The interactions between the quinine sulfate/bisulfate and the guest can be hydrogen bonding, van der Waals interactions, electrostatic interactions, hydrophobic interactions a combination thereof, and the like. Exemplary solid complexes include co-crystals (i.e. a crystalline supramolecular complex), single phase molecular dispersions, and the like. The properties can include solubility, melting point, spectroscopic, etc.
  • The solid complex may include one or more solvate or water molecules in the crystalline lattice (e.g., solvates or hydrates of co-crystals, or a co-crystal further comprising a solvent or water molecule).
  • “Quinine sulfate” and “quinine bisulfate” are inclusive of all crystalline forms including all polymorphs, non-crystalline forms, anhydrous forms, hydrates such as the dihydrate, and solvates unless specifically indicated otherwise. “Quinine sulfate/bisulfate” means quinine sulfate or quinine bisulfate. Specific polymorphs of quinine sulfate include those disclosed in co-pending Provisional Application Ser. No. 61/015,488, entitled “Quinine Sulfate Polymorphs, Processes of Preparing, Compositions and Uses Thereof” incorporated herein by reference in its entirety, specifically quinine sulfate polymorphs A, B, C, D, E, F, G, H, I, J, and K.
  • “Guest” means an organic acid, specifically acetic acid, gentisic acid, DL-mandelic acid, salicylic acid, or DL-tartaric acid.
  • The ratio of quinine sulfate/bisulfate to guest may be for example, 1:1, 1:1.5 and 1:2. In certain embodiments, the ratio is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10 quinine sulfate/bisulfate to guest. In other embodiments, the ratio is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10 guest to quinine sulfate/bisulfate.
  • The solid complexes can be physically distinguished from crystalline quinine sulfate/bisulfate using a variety of analytical tools and characterization methods, such as, for example, Raman spectroscopy, IR spectroscopy (IR, FT-IR), X-ray powder diffraction (XPRD) crystallography, X-ray crystallography, neutron diffraction, Synchrotron radiation, solid state NMR spectroscopy, differential scanning calorimetry (DSC), Thermogravimetric analysis (TGA), Thermogravimetric/infrared analysis (TG-IR), melting point, and heats of fusion.
  • The quinine sulfate/bisulfate solid complexes can be prepared using a variety of methods including antisolvent precipitation, slow cooling of a solution of quinine sulfate and guest, precipitation from a solution of quinine sulfate and guest at a constant temperature, seeding solutions of quinine sulfate and guest with optional cooling, slurrying and the like.
  • Exemplary methods for preparing solid complexes include mechanical and solvent processes. Exemplary mechanical processes include milling/grinding, and extrusion; and exemplary solvent processes include dissolving, partially dissolving (and optionally sonicating) in a common solvent, followed by solvent evaporation or spray-drying; or a combination thereof. Optionally, the process can be conducted under inert atmosphere (e.g., nitrogen, argon atmospheres).
  • In one embodiment, the quinine sulfate solid complex can be prepared by a milling process. The milling process generally involves grinding quinine sulfate and a guest in a mill, e.g., use of a ball mill, jet mill, impact mill, hammer mill, and the like. Optionally, the grinding can be performed with heating. The quinine sulfate or guest can be in crystalline form, solid non-crystalline form, liquid, or the like.
  • The milling process can include grinding for about 10 seconds to about 2 hours, specifically about 1 minute to about 90 minutes, and more specifically about 20 minutes to about 60 minutes.
  • The solvent process generally involves preparing a solution or suspension of quinine sulfate/bisulfate and guest in a solvent system followed by optional removal of the solvent. In the solution process, both quinine sulfate/bisulfate and guest are completely dissolved in the solvent system. In the suspension process, the quinine sulfate/bisulfate or guest can remain partially undissolved.
  • “Solvent system” means a single or a combination of two or more solvents.
  • Suitable solvents for preparing the quinine sulfate/bisulfate solid complex include those that do not adversely affect the stability of the quinine sulfate/bisulfate, guest or solid complex, and are preferably inert. Suitable solvents may be organic, aqueous, or a mixture thereof Suitable organic solvents may be aliphatic alcohols such as methanol (MeOH), ethanol (EtOH), n-propanol, isopropanol (IPA), n-butanol, tert-amyl alcohol (t-AmOH), tert-butyl alcohol, triflouroethanol, and 2-ethoxyethanol, particularly lower alkyl (C1-C6) alcohols; ethers such as tetrahydrofuran (THF), dioxane, methyl-tert-butyl ether, 1,2-dimethoxyethane (DME), and 2-methyl tetrahydrofuran; aliphatic ketones such as acetone, methyl ethyl ketone (MEK), and methyl isobutyl ketone; aliphatic carboxylic esters such as methyl acetate, ethyl acetate (EtOAc), and isopropyl acetate; aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane; aliphatic nitriles such as acetonitrile (MeCN) and propionitrile; chlorinated hydrocarbons such as dichloromethane (DCM), chloroform, and carbon tetrachloride; aliphatic sulfoxides such as dimethyl sulfoxide (DMSO); amides such as dimethylformamide (DMF) and dimethylacetamide (DMA); organic acids such as acetic acid; N-methyl-2-pyrrolidone; pyridine; and the like, as well as mixtures comprising at least one of the foregoing organic solvents. Certain solvents can be used as an anti-solvent to induce crystal formation from solution.
  • Optionally, the solution, prior to any solids formation, can be filtered to remove any undissolved solids, solid impurities and the like prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used.
  • In one embodiment, the solutions or suspensions can be seeded with the desired quinine sulfate solid complex.
  • In one embodiment, the solutions or suspensions can be sonicated.
  • In one embodiment, the solvent system of the solution or suspension of quinine sulfate/bisulfate, guest, and solvent system is removed slowly or rapidly. Rapid removal of the solvent system can be achieved in less than a minute by processes such as spray drying. Slow removal of the solvent system can be achieved in a minute or greater using methods such as evaporation under reduced pressure or evaporation at atmospheric pressure. Removal of the solvent system can be achieved with optional heating.
  • In one embodiment, a quinine sulfate acetic acid solid complex exhibits XRPD peak positions at 8.4, 15.2, 16.6, 17.0, 17.8, 19.3, 20.4, 23.8, 25.2, and 25.7±0.1 degree 2-theta. In another embodiment, a quinine sulfate acetic acid solid complex exhibits the XRPD peak positions in Table 4 below. In yet another embodiment, a quinine sulfate acetic acid solid complex exhibits an X-ray powder diffraction pattern which is substantially similar to FIG. 1. In another embodiment, a quinine sulfate acetic acid solid complex exhibits FT-Raman peaks at 1364, 1429, 1445, and 2954±4 cm−1. In another embodiment, a quinine sulfate acetic acid solid complex exhibits FT-Raman peaks in Table 5 below. In yet another embodiment, a quinine sulfate acetic acid solid complex exhibits a FT-Raman spectrum which is substantially similar to FIG. 2.
  • In one embodiment, a solid complex of quinine sulfate is quinine sulfate acetic acid co-crystal, specifically quinine sulfate acetic acid co-crystal monohydrate (2quinine.H2SO4.CH3COOH.H2O). The quinine sulfate acetic acid co-crystal exhibits water solubility at room temperature of about 2 milligrams per milliliter.
  • In one embodiment, a quinine bisulfate tartaric acid solid complex exhibits XRPD peak positions at 9.4, 10.4, 13.8, 15.2, 15.6, 16.8, 17.4, 18.7, 19.5, and 20.5±0.1 degrees 2-theta. In another embodiment, a quinine bisulfate tartaric acid solid complex exhibits the XRPD peak positions in Table 9 below. In yet another embodiment, a quinine bisulfate tartaric acid solid complex exhibits an X-ray powder diffraction pattern which is substantially similar to FIG. 3. In another embodiment, a quinine bisulfate tartaric acid solid complex exhibits FT-Raman peaks at 767, 1386, 1431, and 1622±4 cm−1. In another embodiment, a quinine bisulfate tartaric acid solid complex exhibits FT-Raman peaks in Table 10 below. In yet another embodiment, a quinine bisulfate tartaric acid solid complex exhibits a FT-Raman spectrum which is substantially similar to FIG. 4.
  • In another embodiment, a solid complex of quinine sulfate/bisulfate is quinine bisulfate tartaric acid co-crystal. The quinine bisulfate tartaric acid co-crystal exhibits solubility in water at room temperature of about 200 milligrams per milliliter.
  • Also disclosed herein are pharmaceutical compositions comprising the quinine sulfate/bisulfate solid complexes prepared herein.
  • Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, powders, and granules. In such solid dosage forms, the solid complex may be admixed with one or more of the following: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders, such as carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f solution retarders, such as paraffin; (g) absorption accelerators, such as quaternary ammonium compounds; (h) wetting agents, such as cetyl alcohol and glycerol monostearate; (i) adsorbents, such as kaolin and bentonite; and (j) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and combinations comprising one or more of the foregoing additives. For capsules and tablets, the dosage forms may also comprise buffering agents.
  • By “oral dosage form” is meant to include a unit dosage form for oral administration. An oral dosage form may optionally comprise a plurality of subunits such as, for example, microcapsules or microtablets. Multiple subunits may be packaged for administration in a single dose.
  • By “subunit” is meant to include a composition, mixture, particle, pellet, etc., that can provide an oral dosage form alone or when combined with other subunits.
  • The compositions can be immediate-release forms or controlled-release forms.
  • By “immediate-release” is meant a conventional or non-modified release in which greater then or equal to about 75% of the active agent is released within two hours of administration, specifically within one hour of administration.
  • By “controlled-release” is meant a dosage form in which the release of the active agent is controlled or modified over a period of time. Controlled can mean, for example, sustained-, delayed- or pulsed-release at a particular time. Alternatively, controlled can mean that the release of the active agent is extended for longer than it would be in an immediate-release dosage form, e.g., at least over several hours.
  • Dosage forms can be combination dosage forms having both immediate-release and controlled-release characteristics, for example, a combination of immediate-release pellets and controlled-release pellets. The immediate-release portion of a combination dosage form may be referred to as a loading dose.
  • Certain compositions described herein may be “coated”. The coating may be a suitable coating, such as, a functional or a non-functional coating, or multiple functional or non-functional coatings. By “functional coating” is meant to include a coating that modifies the release properties of the total composition, for example, a sustained-release coating. By “non-functional coating” is meant to include a coating that is not a functional coating, for example, a cosmetic coating. A non-functional coating can have some impact on the release of the active agent due to the initial dissolution, hydration, perforation of the coating, etc., but would not be considered to be a significant deviation from the non-coated composition.
  • The solid complexes of quinine sulfate and the compositions disclosed herein are useful for example to treat or for the prophylaxis of malaria caused by Plasmodium species (e.g., falciparum, vivax, and the like), uncomplicated Plasmodium falciparum malaria, severe or complicated Plasmodium falciparum malaria; the treatment or prophylaxis of leg muscle cramps (e.g., nocturnal recumbency leg muscle cramps), and the treatment of babesiosis caused by Babesia microti.
  • Malaria is a parasitic disease caused by the Plasmodium species P. falciparum, P. vivax, P. ovale and P. malariae. Malaria parasites are transmitted by female Anopheles mosquitoes. Without being held to theory, it is believed that quinine toxic to the malaria parasite, specifically by interfering with the parasite's ability to break down and digest hemoglobin, thus starving the parasite or causing the build-up of toxic levels of partially degraded hemoglobin.
  • Nocturnal recumbency leg muscle cramps, a common complaint in the elderly, is manifested as painful, involuntary contractions in the lower extremities after recumbency. Quinine can be used for the treatment of leg cramps including those associated with arthritis, diabetes, varicose veins, thrombophlebitis, arteriosclerosis and static foot deformities.
  • Babesiosis is caused by Babesia microti. The definitive host is a tick, in this case the deer tick, Ixodes dammini (I. scapularis). Humans enter the cycle when bitten by infected ticks; during a blood meal, a Babesia-infected tick introduces sporozoites into the human host.
  • The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.
    • EXAMPLES
  • X-ray powder diffraction analyses are performed on an Inel XRG-3000 diffractometer, equipped with a curved position-sensitive detector with a 2-theta range of 120°. Real time data is collected using Cu Ka radiation at a resolution of 0.03° 2-theta. The tube voltage and amperage are set to 40 kV and 30 mA, respectively. Samples are prepared for analysis by packing them into thin-walled glass capillaries. Each capillary is mounted onto a goniometer head that is motorized to permit spinning of the capillary during data acquisition. Instrument calibration is performed daily using a silicon reference standard. Peak lists are generated by using FileMonkey v3.2.0, Notepad v5.1, Dash v3.1, EXCEL 2003, and PatternMatch 2.3.6. The XRPD patterns are background-corrected and prominent peaks are selected with the following parameters in Dash v3.1 (wavelength 1.541874 Å, 15 iterations, 150 window, Monte Carlo, Smooth w/5 window). Peak positions are rounded to the nearest 0.1° 2-theta, relative intensities are rounded to the nearest 1%, peaks with a relative intensity less than 10% are removed, and peaks above 26° 2θ are also removed.
  • Differential scanning calorimetry (DSC) analyses is carried out on a TA Instruments differential scanning calorimeter 2920; calibrated using indium reference. The sample is placed in a standard aluminum DSC pan with an uncrimped lid. The sample cell is equilibrated at 0° C. and heated under nitrogen purge at a rate of 10° C./minute up to a final temperature of 300° C.
  • Thermogravimetry (TG) analyses are carried out on a TA Instruments 2950 thermogravimetric analyzer. The calibration standards are nickel and Alumel™. Each sample is place in an aluminum sample pan and inserted into the TG furnace. Samples are started at ambient and then heated under a stream of nitrogen at a heating rate of 10° C./min, up to a final temperature of 175 or 350° C.
  • Fourier Transform Raman (FT-Raman) spectra are obtained using a FT-Raman 960 spectrometer (Thermo Nicolet) using an excitation wavelength of 1064 nm. Approximately 0.3 W of Nd:YVO4 laser power is used to irradiate the sample. The Raman spectra are measured with a germanium (Ge) detector. The samples are prepared for analysis by placing the material in a glass tube and positioning the tube in a gold-coated tube holder in the accessory. A total of 256 sample scans are collected from 3600-100 cm−1 at a spectral resolution of 4 cm−1, using Happ-Genzel apodization. Wavelength calibration is performed using sulfur. Data are analyzed and peak lists are generated by using Omic v. 7.2 software.
    • Example 1 Preparation of Quinine Sulfate/Bisulfate Solid Complexes: Manual Screen
  • The specific parameters of the manual screen studies are provided in Table 1 below. Generalized procedures for the preparation of the solid complexes are provided below.
  • A generalized milling process involves placing approximately equal amounts of quinine sulfate and respective guest compounds into an agate milling holder with a milling ball for milling at ambient temperature. The sample is dry milled. The sample is milled for specific time intervals (2 and 20 minutes) at 30 Hz using a Retsch MM200 mixer mill. The vial is opened and solids scraped from the side of the milling holder and ball in 5 minutes increments for the 20 minute grinding experiments.
  • Antisolvent Crystallization (AC). Solutions are prepared in various solvents at ambient temperatures and filtered through a 0.2-μm nylon filter. Antisolvent is then added and the solution is allowed to stand at ambient.
  • Ambient Crystallization (AmC). Solutions are prepared in various solvents at ambient temperatures and filtered through a 0.2-μm nylon filter. The solutions are then allowed to stand at ambient.
  • Crash Cool (CC). Solutions are prepared in various solvents at elevated temperatures and filtered through a 0.2-μm nylon filter into a vial. Vials are then either left at ambient or placed in the refrigerator or a freezer.
  • Liquid Diffusion (LD). Solutions were prepared and filtered through a 0.2-μm nylon filter. The filtered solution was allowed to diffuse into an antisolvent in a small glass tube at ambient temperature. The anti-solvent used is miscible with the solvent and the tubes are left vertically and undisturbed at ambient.
  • Slow Cool (SC). Solutions are prepared using various solvents at elevated temperatures and filtered through a 0.2-μm nylon filter into an open vial while still warm. The vial is allowed to cool slowly to room temperature. The presence or absence of solids is noted. If there are no solids present, or if the amount of solids is judged too small for XRPD analysis, the vial is placed in a refrigerator. Again, the presence or absence of solids is noted and if there were none, the vial was placed in a freezer. Solids that formed are isolated by filtration and allowed to dry prior to analysis.
  • Slow Evaporation (SE). Solutions are prepared in various solvents and sonicated between aliquot additions to assist in dissolution. Once a mixture reaches complete dissolution, as judged by visual observation, the solution is filtered through a 0.2-μm nylon filter. The filtered solution is allowed to evaporate at ambient in a vial covered with aluminum foil perforated with pinholes.
  • Slurry. Solutions are prepared by adding enough solids to a given solvent so that excess solids are present. The mixture is then agitated in a sealed vial at ambient.
  • All isolated solids are analyzed by X-ray powder diffraction revealing new XRPD patterns.
  • TABLE 1
    XRPD result
    Guest Solvent Ratio API:guest Method Description
    Acetic acid Acetone — Antisolvent precipitation Acetic acid cocrystal
    monohydrate
    White solid, small needles
    Acetic acid — — Milling/20 minutes Acetic acid cocrystal
    monohydrate
    White solid
    Acetic acid — — Milling/20 minutes Acetic acid cocrystal
    monohydrate
    Off-white solid, irregular
    particles
    DL-Tartaric Ethanol 2:1 Slow cool (~70° C. to freezer) Quinine bisulfate tartaric
    acid acid cocrystal
    White solid, thin needles
    DL-Tartaric Ethanol 2:1 Complete dissolution Quinine bisulfate tartaric
    acid followed by precipitation and acid cocrystal + peaks
    slurry at ~70° C. White solid, irregular
    particles
    DL-Tartaric Ethanol 2:1 Complete dissolution Quinine bisulfate tartaric
    acid followed by precipitation and acid cocrystal
    slurry at ~70° C. Off-white solid, irregular
    particles
    • Example 2a Preparation of Quinine Sulfate Acetic Acid Solid Complex-Milling
  • About 103 milligrams (mg) of quinine sulfate is milled with 20 microliters of glacial acetic acid in a ceramic sample holder for 20 minutes on a ball mill. Off-white solids are obtained and analyzed by XRPD, 1H NMR, Elemental analysis, and DSC (Table 2).
  • TABLE 2
    Analytical
    Technique Results
    XRPD Quinine sulfate acetic acid cocrystal monohydrate
    1H NMR Similar to quinine sulfate
    0.5 moles of acetic acid per mole of quinine
    Elemental Experimental: 60.18 (% C); 6.76 (% H); 6.64 (% N);
    Analysis 3.97 (% S)
    Theoretical: 61.15 (% C); 6.84 (% H); 6.79 (% N); 3.89 (% S)
    Composition: Quinine sulfate•acetic acid•H2O
    DSC Endotherms: 93° C., 213° C. (onset: 208° C.)
    • Example 2b Preparation of Quinine Sulfate Acetic Acid Solid Complex-Antisolvent Precipitation
  • Approximately 4 grams of quinine sulfate is dissolved in 8 mL of acetic acid. Antisolvent acetone, 43 mL, is added and white precipitation forms upon stirring at ambient. Solids (3.5 g) are collected by vacuum filtration, followed by an air dry over night. The solids are analyzed by 1H NMR, DSC, and TG (Table 3); and by XRPD (FIG. 1, peak listing Table 4) and FT-Raman (FIG. 2, peak listing Table 5).
  • TABLE 3
    Analytical
    Technique Results
    XRPD Quinine sulfate acetic acid cocrystal monohydrate
    1H NMR Similar to quinine sulfate
    0.4 moles of acetic acid per mole of quinine
    TG 2.7% weight loss up to 120° C.
    DSC Endotherms: 97° C., 205° C., 213° C.
  • TABLE 4
    XRPD peaks
    Position (°2-theta ± 0.1 °2-theta) I/Io relative intensity
    8.4 100
    15.2 30
    16.6 58
    17.0 92
    17.8 18
    18.3 11
    19.3 14
    20.4 92
    23.8 12
    25.2 15
    25.7 45
  • TABLE 5
    FT-Raman peaks
    Region 3600.4 to 98.3 cm−1
    Absolute threshold 3.606
    Sensitivity 100
    (cm−1) Intensity
     123.8 37.026
     148.5 57.506
     181.3 23.671
     225.7 10.321
     246.9 8.29
     263.8 9.28
     330.9 5.841
     353.1 8.309
     376.3 5.549
    401  16.132
     438.1 17.794
     465.5 9.378
     527.9 13.265
     541.1 7.159
     553.2 15.964
     577.9 10.345
     625.3 5.534
     642.8 4.922
     665.1 5.423
     696.5 4.534
     720.3 3.915
     763.2 22.446
     775.1 19.159
     790.1 24.522
     802.5 19.666
    832  15.108
     856.2 8.995
     868.5 5.754
     883.3 5.568
     921.6 7.752
     937.9 4.568
     967.8 8.297
     983.2 19.316
    1007.6 8.918
    1017.5 8.026
    1030.4 7.854
    1044.8 6.513
    1056.3 13.306
    1078.3 9.789
    1100.2 7.367
    1132.1 10.724
    1146.6 4.041
    1168.1 6.011
    1177.9 8.423
    1186   6.972
    1204.8 10.279
    1229.2 25.821
    1241.9 11.058
    1267.7 11.253
    1277.9 10.374
    1303.9 18.795
    1312.8 21.092
    1364   248.267
    1404.8 10.043
    1428.8 41.254
    1445.3 40.024
    1508.9 9.246
    1574.8 14.812
    1592.5 23.513
    1619.9 19.464
    1643.8 21.718
    1726.8 3.796
    2836.8 8.329
    2860   6.294
    2884.9 11.968
    2954.3 59.396
    2974.3 34.394
    2992.4 34.988
    3004.7 32.4
    3046.1 22.768
    3074.8 29.228
    — —
    — —
    — —
    — —
    — —
    — —
    — —
    — —
    — —
    • Example 2c Preparation of Quinine Sulfate Acetic Acid Solid Complex-Single Crystal
  • Attempts to prepare a single crystal of quinine sulfate acetic acid solid complex are carried out in a variety of solvent systems and procedures according to Table 6 below. Single crystal structure determination was made from material prepared from liquid diffusion in ethyl acetate provides quinine sulfate acetic acid cocrystal monohydrate.
  • TABLE 6
    Solvent Conditiona Descriptionb
    Acetone LD Thin needles with B and E
    Acetone AC Thin needles and fibers with B and E
    Acetone SE Irregular particles and fibers with B and E
    Acetone SE Irregular particles and fibers with B and E
    ACN SE Fibers
    ACN SE Irregular Particles
    ACN AC Thin needles and fibers with B and E
    DCM SE Irregular particles and fibers with B and E
    DCM SE Fibers with B and E
    DCM SC Small particles with B and E
    (RT to rfg)
    DCM SC Small particles with B and E
    (RT to rfg)
    Dioxane AC Small needles with B and E
    Dioxane AC Small needles with B and E
    Dioxane SC Small needles with B and E
    (RT to rfg)
    Dioxane SC Small needles with B and E
    (RT to rfg)
    Dioxane SE Fibers with B and E
    EtOAc AC Irregular Particles
    EtOAc AC Irregular Particles
    EtOAc SE Irregular particles and fibers with B and E
    EtOAc SE Clear gel
    EtOAc AC Thin needles and fibers with B and E
    EtOAc LD Needles with B and E
    EtOAc LD Long needles with B and E
    EtOAc LD Long needles with B and E
    EtOAc LD Long needles with B and E
    EtOAc LD Long needles with B and E
    EtOAc LD Long needles with B and E
    Nitromethane SE Fibers with B and E
    Nitromethane SE Fibers with B and E
    THF AC Irregular Particles
    THF AC Irregular Particles
    THF AC Small needles with B and E
    THF AC Small needles with B and E
    THF SC Small needles with B and E
    (RT to rfg)
    THF SC Small needles with B and E
    (RT to rfg)
    Toluene SE Fibers with B and E
    Toluene SE Fibers with B and E
    Toluene Slurry/RT Brown oil
    aSE = slow evaporation, SC = slow cool, AC = antisolvent crystallization, LD = liquid diffusion, RT = room temperature, rfg = refrigerator
    bB = birefringence, E = extinction
    • Example 3 a Preparation of Quinine Bisulfate Tartaric Acid Solid Complex
  • About 100 mg of quinine sulfate and 38 mg of tartaric acid (1:2) are completely dissolved in 1.0 ml of ethanol at about 70° C. Precipitation formed and the mixture is allowed to slurry on a stir plate overnight. Off-white solids (30 mg) are collected by vacuum filtration and analyzed by XRPD, 1H NMR, Elemental analysis, and DSC (Table 7).
  • TABLE 7
    Analytical
    Technique Results
    XRPD Quinine bisulfate tartaric acid cocrystal
    1H NMR Chemical structure of quinine appears intact
    0.9 mole of DL-tartaric acid per mole of quinine
    Elemental Analysis Experimental: 50.42 (% C); 5.55 (% H);
    4.66 (% N); 5.65 (% S)
    Theoretical: 50.34 (% C); 5.63 (% H); 4.89 (% N);
    5.60 (% S)
    Composition: Quinine bisulfate•tartaric acid
    DSC Broad exotherm: 75° C.
    Endotherm: 200° C. (onset 195° C.)
    • Example 3b Large Scale Preparation of Quinine Bisulfate Tartaric Acid Solid Complex
  • Approximately 5 grams of quinine sulfate and 1.9 gram of tartaric acid (1:2) were completely dissolved in 50 mL of hot ethanol (˜70° C.). Precipitation formed upon stirring at ˜70° C. over night. Solids (2.8 g) are then collected by vacuum filtration. The material is then further dried in a vacuum oven at room temperature for 4 days. 1H NMR, DSC, and TG analyses are performed (Table 8). The solids are analyzed by XRPD (FIG. 3, peak listing Table 9) and FT-Raman (FIG. 4, peak listing Table 10).
  • TABLE 8
    Analytical
    Technique Results
    XRPD Quinine bisulfate tartaric acid cocrystal
    TG 1.4% weight loss up to 80° C.
    1H NMR Chemical structure of quinine appears intact
    0.9 mole of tartaric acid per mole of quinine
    0.1 mole of ethanol
    TG 1.1% weight loss up to 70° C.
    DSC Endotherms: 63° C., 192° C.
  • TABLE 9
    XRPD peaks
    Position (°2-theta ± 0.1 °2-theta) I/Io relative intensity
    9.4 53
    10.4 28
    13.8 17
    15.2 17
    15.6 34
    16.8 42
    17.4 100
    18.7 50
    19.5 85
    20.0 16
    20.5 30
    20.7 25
    21.6 18
    22.8 25
    23.3 12
    24.0 24
    24.6 13
    25.7 16
  • TABLE 10
    FT-Raman peaks
    Region 3600.4 to 98.3 cm−1
    Absolute threshold 8.828
    Sensitivity 100
    (cm−1) Intensity
    111 99.392
    133.2 99.909
    169.5 106.089
    240.2 22.174
    277.5 19.294
    335.1 14.144
    358 19.104
    404.1 34.553
    432.9 44.957
    464.5 20.302
    503.1 10.467
    528.8 39.555
    540.8 26.865
    555.4 32.47
    576.3 25.619
    598 11.638
    613.7 11.159
    632.7 8.934
    646.9 12.792
    661.1 10.464
    668.5 10.43
    696.5 11.231
    717.3 15.219
    743.6 15.375
    767 68.064
    790.1 31.741
    804.5 37.417
    831.9 29.316
    844 18.927
    859.3 21.095
    885.6 17.242
    919 17.646
    945.5 22.74
    979.2 25.831
    1019 25.493
    1055.1 25.074
    1079.5 20.105
    1099.7 26.919
    1132.1 15.194
    1153.4 22.046
    1186.9 31.809
    1210 60.663
    1231.3 32.378
    1246.5 31.26
    1265.4 32.966
    1288.3 27.932
    1305.5 32.834
    1322.9 22.557
    1386.4 455.802
    1431.1 127.991
    1442.1 71.226
    1502.8 46.972
    1552.6 17.441
    1606.4 52.475
    1621.7 68.89
    1642.6 53.877
    1703.9 10.479
    1769.3 11.013
    2844.1 13.271
    2860.4 11.149
    2900.7 29.204
    2928.8 32.758
    2962.1 56.771
    2980.8 41.561
    3011.8 33.653
    3035.3 17.744
    3071 24.63
    3114.9 12.743
    • Example 3c Preparation of Quinine Bisulfate Tartaric Acid Solid Complex-Single Crystal
  • Attempts to prepare a single crystal of quinine bisulfate tartaric acid solid complex are carried out in a variety of solvent systems and procedures according to Table 11 below.
  • TABLE 11
    Solvent Condition Description
    EtOH/MeOH Crash cool ~70 C. to room temp., Clustered blades
    slow evaporation room temp.
    EtOH/MeOH Crash cool ~70 C. to room temp., Chunks
    fast evaporation room temp.
    MeOH* Slow cool ~70 C. to room temp. Blades, some clustered
    *50 mg quinine bisulfate/tartaric acid cocrystal and 26 mg DL-tartaric acid are dissolved in hot methanol.
  • Single crystal analysis of material obtained from crystallization in methanol reveals the material is a quinine bisulfate tartaric acid cocrystal.
  • The terms “comprising”, “having”, “including”, and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to”). The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term “or” means “and/or”. The endpoints of all ranges directed to the same component or property are inclusive and independently combinable.
  • Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.
  • Embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims (16)

1. A solid complex, comprising:
quinine sulfate/bisulfate and
a guest, wherein the guest is acetic acid or DL-tartaric acid.
2. The solid complex of claim 1, wherein the solid complex is in the form of a hydrate.
3. The solid complex of claim 1, wherein the solid complex is quinine sulfate acetic acid solid complex comprising one or more of the following:
XRPD peak positions at 8.4, 15.2, 16.6, 17.0, 17.8, 19.3, 20.4, 23.8, 25.2, and 25.7±0.1 degree 2-theta;
XRPD peak positions similar to those in Table 4;
an X-ray powder diffraction pattern which is substantially similar to FIG. 1;
FT-Raman peaks at 1364, 1429, 1445, and 2954±4 cm−1;
FT-Raman peaks substantially similar to those in Table 5; or
FT-Raman spectrum which is substantially similar to FIG. 2.
4. The solid complex of claim 1, wherein the solid complex is quinine sulfate acetic acid co-crystal monohydrate.
5. The solid complex of claim 1, wherein the solid complex is quinine bisulfate tartaric acid solid complex comprising one or more of the following:
XRPD peak positions at 9.4, 10.4, 13.8, 15.2, 15.6, 16.8, 17.4, 18.7, 19.5, and 20.5±0.1 degrees 2-theta;
XRPD peak positions similar to those in Table 9;
an X-ray powder diffraction pattern which is substantially similar to FIG. 3;
FT-Raman peaks at 767, 1386, 1431, and 1622±4 cm−1;
FT-Raman peaks substantially similar to those in Table 10; or
FT-Raman spectrum which is substantially similar to FIG. 4.
6. The solid complex of claim 1, wherein the solid complex is quinine bisulfate tartaric acid cocrystal.
7. A composition, comprising:
a solid complex comprising quinine sulfate/bisulfate and a guest, wherein the guest is acetic acid or DL-tartaric acid; and
a pharmaceutically acceptable excipient.
8. The composition of claim 7, wherein the composition is a solid oral dosage formulation.
9. A method of treating a patient, comprising:
administering to a patient in need thereof the solid complex of claim 1.
10. A method of treating a patient, comprising:
administering to a patient in need thereof the composition of claim 7.
11. The method of claim 9, wherein the solid complex is used to treat malaria caused by Plasmodium species, uncomplicated Plasmodium falciparum malaria, severe or complicated Plasmodium falciparum malaria, malaria caused by Plasmodium vivax, leg muscle cramps, or babesiosis; or for the prophylaxis of malaria or leg muscle cramps.
12. The method of claim 10, wherein the composition is used to treat malaria caused by Plasmodium species, uncomplicated Plasmodium falciparum malaria, severe or complicated Plasmodium falciparum malaria, malaria caused by Plasmodium vivax, leg muscle cramps, or babesiosis; or for the prophylaxis of malaria or leg muscle cramps.
13. A method of preparing a solid complex, comprising one of the following:
i.) milling a combination of quinine sulfate and acetic acid to form quinine sulfate acetic acid solid complex;
ii) preparing quinine sulfate acetic acid solid complex by liquid diffusion in ethyl acetate;
iii) crystallizing a solid complex from a solution containing quinine sulfate, a guest, and optionally a solvent system with optionally evaporating the solvent system from the solution, wherein the guest is DL-tartaric acid;
iv) adding an anti-solvent to a solution containing quinine sulfate, a guest, and optionally a solvent system; and precipitating a quinine sulfate solid complex, wherein the guest is acetic acid; or
v) dissolving quinine sulfate and tartaric acid in a lower alkyl alcohol with heating, and allowing the solid complex to precipitate.
14. The method of claim 13, wherein iii) further comprises seeding the solution.
15. The method of claim 13, wherein the anti-solvent of iv) is acetone.
16. The method of claim 13, wherein iv) further comprises slurrying the quinine sulfate, guest, and solvent system.
US12/491,311 2008-06-30 2009-06-25 Quinine sulfate/bisulfate solid complex; methods of making; and methods of use thereof Expired - Fee Related US8258155B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/491,311 US8258155B2 (en) 2008-06-30 2009-06-25 Quinine sulfate/bisulfate solid complex; methods of making; and methods of use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7678008P 2008-06-30 2008-06-30
US12/491,311 US8258155B2 (en) 2008-06-30 2009-06-25 Quinine sulfate/bisulfate solid complex; methods of making; and methods of use thereof

Publications (2)

Publication Number Publication Date
US20090326005A1 true US20090326005A1 (en) 2009-12-31
US8258155B2 US8258155B2 (en) 2012-09-04

Family

ID=41448219

Family Applications (1)

Application Number Title Priority Date Filing Date
US12/491,311 Expired - Fee Related US8258155B2 (en) 2008-06-30 2009-06-25 Quinine sulfate/bisulfate solid complex; methods of making; and methods of use thereof

Country Status (2)

Country Link
US (1) US8258155B2 (en)
WO (1) WO2010002675A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090163540A1 (en) * 2007-12-20 2009-06-25 Tong Sun Quinine Sulfate Polymorphs, Processes of Preparing, Compositions and Uses Thereof

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US501066A (en) * 1893-07-11 Edouard grimaux
US20020114844A1 (en) * 2000-11-09 2002-08-22 Hanna Mazen H. Particle formation methods and their products
US20040176335A1 (en) * 2003-01-21 2004-09-09 Childs Scott L. Novel cocrystallization
US20050181041A1 (en) * 2003-12-09 2005-08-18 Medcrystalforms, Llc Method of preparation of mixed phase co-crystals with active agents
US20060243831A1 (en) * 2005-04-29 2006-11-02 Javier Gonzalez-Zugasti Methods and systems for co-crystal synthesis
US20060263427A1 (en) * 2005-05-03 2006-11-23 Roberts Richard H Quinine formulations
US20070026078A1 (en) * 2002-02-15 2007-02-01 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions
US20070059356A1 (en) * 2002-05-31 2007-03-15 Almarsson Oern Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen
US20070088508A1 (en) * 2005-09-28 2007-04-19 Scott Childs Cocrystallization methods
US20070212683A1 (en) * 2006-02-27 2007-09-13 Connelly Patrick R Co-crystals and pharmaceutical compositions comprising the same
US20090163540A1 (en) * 2007-12-20 2009-06-25 Tong Sun Quinine Sulfate Polymorphs, Processes of Preparing, Compositions and Uses Thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078163A2 (en) 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen
WO2004060347A2 (en) 2002-09-03 2004-07-22 Transform Pharmaceuticals, Inc. Pharmaceutical propylene glycol solvate compositions
JP4923182B2 (en) 2003-02-28 2012-04-25 マクニール−ピーピーシー・インコーポレーテツド Celecoxib and nicotinamide co-crystal and pharmaceutical composition containing the co-crystal
EP2292585B1 (en) 2004-03-12 2016-04-27 Aptuit (West Lafayette), LLC Screening for solid forms by ultrasound crystallization and cocrystallization using ultrasound

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US501066A (en) * 1893-07-11 Edouard grimaux
US20020114844A1 (en) * 2000-11-09 2002-08-22 Hanna Mazen H. Particle formation methods and their products
US20070026078A1 (en) * 2002-02-15 2007-02-01 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions
US20070059356A1 (en) * 2002-05-31 2007-03-15 Almarsson Oern Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen
US20040176335A1 (en) * 2003-01-21 2004-09-09 Childs Scott L. Novel cocrystallization
US20050181041A1 (en) * 2003-12-09 2005-08-18 Medcrystalforms, Llc Method of preparation of mixed phase co-crystals with active agents
US20060243831A1 (en) * 2005-04-29 2006-11-02 Javier Gonzalez-Zugasti Methods and systems for co-crystal synthesis
US20060263427A1 (en) * 2005-05-03 2006-11-23 Roberts Richard H Quinine formulations
US20070088508A1 (en) * 2005-09-28 2007-04-19 Scott Childs Cocrystallization methods
US20070212683A1 (en) * 2006-02-27 2007-09-13 Connelly Patrick R Co-crystals and pharmaceutical compositions comprising the same
US20090163540A1 (en) * 2007-12-20 2009-06-25 Tong Sun Quinine Sulfate Polymorphs, Processes of Preparing, Compositions and Uses Thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
West, Solid State CHemistry and Its Applications, WIley, New York, pp 358,365, 1988. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090163540A1 (en) * 2007-12-20 2009-06-25 Tong Sun Quinine Sulfate Polymorphs, Processes of Preparing, Compositions and Uses Thereof

Also Published As

Publication number Publication date
WO2010002675A2 (en) 2010-01-07
WO2010002675A3 (en) 2010-05-06
US8258155B2 (en) 2012-09-04

Similar Documents

Publication Publication Date Title
RU2497820C2 (en) Crystalline forms and two solvate forms of lactic acid salts 4-amino-5-fluorine-3-[5-(4-methylpiperazin-1-yl)-1-h-benzimidazol-2-yl]quinoline-2(1h)one
CN107531682B (en) Maleate salts of B-RAF kinase inhibitors, crystalline forms thereof, methods of preparation and uses
US6242460B1 (en) Zolpidem salt forms
EP2639234A1 (en) Crystalline 6,7-unsaturated-7-carbamoyl morphinane derivative, and method for producing same
TWI815820B (en) Solid forms of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-n-benzylacetamide
JP2011037844A (en) 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-n-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzene sulfonate, crystal of the same, polymorphs thereof, and methods for producing them
US8258155B2 (en) Quinine sulfate/bisulfate solid complex; methods of making; and methods of use thereof
KR20130004370A (en) Novel polymorphs of azabicyclohexane
CN113816952A (en) Salt and crystal form of morpholine derivative, preparation method, pharmaceutical composition and application thereof
JP5744017B2 (en) Crystals of thienopyrimidine derivatives
NL1014634C1 (en) Zolpidem salts.
JP2020073523A (en) Salts and polymorphs of substituted imidazopyridinyl-aminopyridine compounds
US8003700B2 (en) Colchicine solid complex; methods of making; and methods of use thereof
CA3067271A1 (en) Crystalline forms of ponatinib hydrochloride
US20090163540A1 (en) Quinine Sulfate Polymorphs, Processes of Preparing, Compositions and Uses Thereof
HUE028550T2 (en) Polymorphs of 6-(piperidin-4-yloxy)-2h-isoquinolin-1-one hydrochloride
EP3812384B1 (en) Maleate of benzothiophene compound, crystalline form thereof and use thereof
JP2023533874A (en) PN6047 hydrochloride polymorph
Sirikun et al. Cocrystallization of Artemisinin and Amodiaquine Hydrochloride
US8519002B2 (en) Colchicine solid complex; methods of making; and methods of use thereof
JPH0529227B2 (en)
HK1234747B (en) Salts and polymorphs of a substituted imidazopyridinyl-aminopyridine compound
FR2967413A1 (en) COMPOUND 8-OXO-9- [3- (1H-BENZIMIDAZOL-2-YLOXY) -PHENYL] -4,5,6,7,8,9-HEXAHYDRO-2H-PYRROLO [3,4-B] QUINOLIN-3 - ETHYL CARBOXYLATE, SALT, CRYSTALLINE FORM, CO-CRYSTAL, FORMULATION, METHODS OF PREPARATION, MEDICAMENT APPLICATION, PHARMACEUTICAL COMPOSITIONS, AND NOVEL USE, IN PARTICULAR AS THE INHIBITOR OF AURORA KINASES.

Legal Events

Date Code Title Description
AS Assignment

Owner name: MUTUAL PHARMACEUTICAL COMPANY, INC., PENNSYLVANIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SUN, TONG;WATSON, SHAWN;LAI, WEI;AND OTHERS;REEL/FRAME:023050/0352;SIGNING DATES FROM 20090109 TO 20090120

Owner name: MUTUAL PHARMACEUTICAL COMPANY, INC., PENNSYLVANIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SUN, TONG;WATSON, SHAWN;LAI, WEI;AND OTHERS;SIGNING DATES FROM 20090109 TO 20090120;REEL/FRAME:023050/0352

AS Assignment

Owner name: UBS AG, STAMFORD BRANCH, AS COLLATERAL AGENT,CONNE

Free format text: PATENT SECURITY AGREEMENT;ASSIGNOR:MUTUAL PHARMACEUTICAL COMPANY, INC.;REEL/FRAME:023424/0896

Effective date: 20091022

Owner name: UBS AG, STAMFORD BRANCH, AS COLLATERAL AGENT, CONN

Free format text: PATENT SECURITY AGREEMENT;ASSIGNOR:MUTUAL PHARMACEUTICAL COMPANY, INC.;REEL/FRAME:023424/0896

Effective date: 20091022

AS Assignment

Owner name: MUTUAL PHARMACEUTICAL COMPANY, INC., A PENNSYLVANI

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:UBS AG, STAMFORD BRANCH, A SWISS BANKING INSTITUTION;REEL/FRAME:026700/0240

Effective date: 20110721

STCF Information on status: patent grant

Free format text: PATENTED CASE

AS Assignment

Owner name: MPC OLDCO, INC., PENNSYLVANIA

Free format text: CHANGE OF NAME;ASSIGNOR:MUTUAL PHARMACEUTICAL COMPANY, INC.;REEL/FRAME:029377/0901

Effective date: 20120921

AS Assignment

Owner name: MUTUAL PHARMACEUTICAL COMPANY, INC., PENNSYLVANIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:MPC OLDCO, INC.;REEL/FRAME:029526/0361

Effective date: 20121211

FPAY Fee payment

Year of fee payment: 4

AS Assignment

Owner name: SUN PHARMACEUTICAL INDUSTRIES, INC., NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:MUTUAL PHARMACEUTICAL COMPANY, INC.;REEL/FRAME:040017/0158

Effective date: 20161004

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20200904